Solid organ transplantation can be life?saving. However, immunosuppression necessary to prevent rejection increases the incidence of cutaneous squamous cell carcinoma (cSCC) 65?250 fold. Current treatments for solid organ transplant recipients (SOTRs) are largely surgical, which can be disfiguring and impact quality of life. There is a huge need for a safe and effective chemoprevention agent for cSCC in SOTRs. The RAF?MEK?ERK signaling pathway plays a key role in cSCC tumorigenesis. Therefore, we identified a novel soft (metabolically labile) MEK inhibitor, NFX?179, which we have formulated into a stable, topical gel. We have demonstrated in minipigs and rodents that topical NFX?179 inhibits p?ERK (a downstream biomarker of RAS/MAPK signaling) in the skin but is efficiently cleared from circulation, thereby minimizing systemic toxicities observed with oral MEK inhibitors. We have demonstrated that topical NFX?179 is an effective chemoprevention agent in a well?established UV?driven mouse model of cSCC. We are seeking funding to (a) determine if topical NFX?179 gel penetrates human cSCC explants and (b) evaluate the durability of the chemoprevention response in the cSCC mouse model. Data from these studies will support advancement into a clinical trial to evaluate topical NFX?179 as chemopreventive agent in SOTRs.